- Email: [email protected]
Margin Assessment of Cutaneous Melanoma
33 Margin Assessment of Cutaneous Melanoma Klaus J. Busam
OUTLINE Guidelines for Melanoma Margins, 398 Tissue Processing and Margin Review, 399 Conventional Elliptical Excisions, 400 Mohs Surgery, 401 Staged Excision, 401
Pitfalls in Margin Assessment, 403 Margin Reporting, 403
Once a diagnosis of primary cutaneous melanoma has been established by a pathologist, the treatment of choice is usually complete removal by surgical excision. Surgery is to accomplish two goals: (a) to permit complete assessment of the entire tumor for prognostic purposes and (b) to minimize risk for metastasis. For in situ melanomas complete surgical removal is curative. If the primary melanoma is confined to the epidermis (in situ) and has implicitly not yet invaded dermis and vascular structures, there should be no risk for distant recurrence. There are cases of reported melanoma in situ and subsequent recurrence due to occult invasion, but the diagnosis of melanoma in situ was simply incorrect. Invasion had occurred but was not detected due to insufficient histopathologic sampling, regression, or interpretative errors. Surgery may also be curative for some lesions of invasive melanoma. The probability of curative surgery is higher for tumors with prognostically favorable (e.g., thickness < 0.5 mm, no mitosis, no ulceration) than unfavorable features. When the prognosis is known to be unfavorable (e.g., detection of lymphatic invasion on biopsy), or even when metastatic spread is already evident clinically (e.g., visible in-transit metastasis, palpable lymph node metastasis), there is still a rationale for surgical excision. Removing a high-risk primary melanoma or tumor already known to have metastasized makes sense because the primary tumor continues to pose a threat for spreading tumor cells to distant sites and/ or local tissue damage (ulceration and invasion of deep tissue structures, with risk for infection, nerve or vascular injury with pain, bleeding, or loss of function).
Guidelines have been proposed for surgical margins based on historic practice, some published data on the subject, and consensus among clinicians selected to serve on panels.1–3 These guidelines have varied over the years. There has been a general trend toward narrower margins for melanoma as it has become apparent, for example, that wide excisions with 5-cm margins for invasive melanoma do not offer any advantage over a 1- or 2-cm margin for survival or risk for local recurrence.4,5 Furthermore, for 1- to 2-mm thick primary melanomas, a 1-cm margin often seems to suffice.6 On the other hand, for melanoma in situ it has also become apparent that some lesions, in particular lentigo malignas, not uncommonly require a 7- to 10-mm or occasionally even wider clinical margin for successful clearance (Table 33.1).7,8 With regard to guidelines, a few comments are in order. First, the margin metrics reflect clinical (Figs. 33.1 and 33.2), not histopathologic, measurements (Fig. 33.3). Second, the purpose of the guidelines of clinical margins is to suggest a rim of tissue for a given melanoma thickness that will achieve a final histopathologically confirmed negative margin at a high probability. It is not the goal or clinically necessary that the tumor be surrounded by a clearance of 5 mm or more of pathologically confirmed normal tissue. For example, when a melanoma in situ has been excised with a clinical measurement of 5 mm and there is a rim of normal skin throughout the periphery of the excision specimen, the surgical margin should be classified as negative and adequate, even if the histopathologic clearance is less than 5 mm, which is often the case, especially when residual melanoma in situ is present (Fig. 33.4). The purpose of the guidelines is that following them will often yield a negative margin (Fig. 33.5). Sometimes, however, there is such a broad subclinical extent that the margin is unexpectedly positive or too narrow (Fig. 33.6). If the clinical goal was to remove the tumor with a negative margin, and additional tissue can be taken with limited or no extra morbidity to the patient, an additional surgical procedure is then in order to achieve that goal. Not uncommonly, following the margin guidelines will yield an unnecessarily wide clearance, and in retrospect one wonders whether a smaller excision would not have sufficed (Fig. 33.7). Second, guidelines are guidelines, not mandates. They apply to most but not all lesions or clinical and personal circumstances. Compromises
GUIDELINES FOR MELANOMA MARGINS When the goal is to remove a primary melanoma surgically, the question arises how widely around the clinically visible lesion or biopsy site should the excision margin be drawn to ensure complete removal of the tumor (in practical terms a histopathologically confirmed negative margin). For some melanomas (e.g., discrete pigmented lesion) there is a good correlation between the clinical and microscopic margin assessment. For other melanomas, however, there is subclinical (clinically invisible or poorly visible, but microscopically confirmed) extension of the tumor in the horizontal plane beyond the area of skin clinically thought to represent melanoma.
398
CHAPTER 33 Margin Assessment of Cutaneous Melanoma
Keywords margin reporting guidelines Mohs staged excision
398.e1
CHAPTER 33 Margin Assessment of Cutaneous Melanoma
399
may need to be made to balance the goal of a negative margin with the goal of minimizing morbidity and maximizing quality of life.
TISSUE PROCESSING AND MARGIN REVIEW Whether or not a melanoma has been entirely removed is assessed by microscopic review of an excision specimen. A margin is determined negative if there is only normal tissue and no tumor seen at the outermost rim of the surgical excision specimen (side and deep margin in a twodimensional view). The accuracy of the margin assessment depends on adequate orientation, processing, and competent microscopic review of the tissue.
TABLE 33.1 AAD Endorsed Margin
Recommendations for Melanoma Tumor Thickness
Margin
Melanoma in situ Melanoma ≤1 mm in thickness Melanoma >1 mm and <2 mm in thickness Melanoma >2 mm in thickness
5–10 mm 1 cm 1–2 cm 2 cm
Fig. 33.1 Clinical measurement of a 5-mm margin for surgical excision of a previously biopsied and diagnosed melanoma in situ. (Courtesy Dr. Erica Lee.)
AAD, American Academy of Dermatology.
A
B
C
D Fig. 33.2 Clinical measurement of a 2-cm margin for a surgical excision of a pT3b melanoma. (A) Prior biopsy site. (B) Longitudinal axis of elliptical excision. (C) Measuring 2-cm distance from biopsy site for side margin. (D) Marking of the ellipse of skin to be excised. (Courtesy Dr. Daniel Coit.)
400
SECTION VII Margin Assessment of Melanomas
Conventional Elliptical Excisions
Fig. 33.3 Histopathologic measurement of margin clearance. Note the difference in cell density between melanoma in situ and normal surrounding skin.
Fig. 33.4 Residual melanoma at the site of a scar (melanocytes are seen in red–IHC for melan-A). The nearest distance of the edge of the melanoma in situ to the nearest side margin measures (measure microscopically) is 3.5 mm.
Fig. 33.5 Histopathology of the excision of a pT2a superficial spreading melanoma with a negative margin. The melanoma is surrounded by a rim of histopathologically confirmed normal skin.
The majority of surgical excisions are elliptical specimens (Fig. 33.8). Typically tissue slides are taken perpendicular to the longitudinal plane of the ellipse, in serial intervals from one end of the ellipse to the other. For precise margin mapping, the specimen should be oriented. This can be accomplished by attaching stitches or other marks (ink) to the specimen (e.g., long stitch indicating the 12 o’clock margin). A corresponding image (digital or print) of the clinical lesion and gross specimen is helpful to avoid misorientation. Often specimens are oriented in a clockwise fashion, so that a microscopically confirmed positive margin can be precisely identified (e.g., positive 3 o’clock margin). If the specimen is received in the pathology laboratory with orientation marks, it should be inked, best in at least two colors identifying the two different sides of an elliptical excision (e.g., medial vs. lateral or 3 o’clock vs. 9 o’clock). The gross description should clearly specify what color ink is used for which margin, such as “the margin is inked black from 12 to 6 o’clock along 3 o’clock and inked blue from 6 to 12 o’clock along 9 o’clock.” Excisional biopsies or small excisions should be submitted entirely for histopathologic margin assessment. Small excisions are usually serially sectioned (“bread-loafed”) from one end (usually the tip of the elliptically shaped specimen surface) to the other with a sectioning knife or sharp blade held perpendicular to the side margins. For large excisions, especially for re-excisions with a previously negative albeit narrow margin, it is not necessary to submit all the tissue for processing. One may focus the tissue sampling on the area most likely to be positive (e.g., grossly visible lesion near a margin or skin surrounding the prior surgical site). Assessing the margins of a melanoma by conventional elliptical excision is fairly accurate and works well in most cases of clinically visible pigmented lesions. With serial bread-loaf sections taken perpendicular to the side and deep margin, one can readily assess the relationship of the tumor to side and deep margins and assess the clearance. Positive margins are uncommon and usually related to unexpected subclinical extension of the tumor or suboptimal surgical technique. False-negative margins (margin status reported as negative,
A
B Fig. 33.6 Histopathology of the excision of a pT2a superficial spreading melanoma. (A) In spite of a clinical measurement of a 1-cm margin, subclinical (clinically not visible) melanoma in situ extends to a side margin. (B) Although the melanoma in situ is not directly transected at the peripheral side margin in this section, it extends so close to the side margin that the margin status should not be reported as negative. It should be regarded as most likely positive.
CHAPTER 33 Margin Assessment of Cutaneous Melanoma but residual tumor persists, continues to grow and locally recurs) are rare. They may be related to suboptimal grossing, embedding, or sectioning and related failure to sample the positive margin, or failure of the pathologist to adequately recognize a histopathologically subtle positive margin.
Mohs Surgery Mohs surgery has been advocated as a surgical excision method for comprehensive margin assessment.7 Intraoperatively, the dermatologic surgeon takes en face layers of tissue around the entire tumor and microscopically assesses for the presence or absence of tumor using frozen sections (Fig. 33.9). If a layer contains tumor, an additional layer is taken. If no tumor is seen, the corresponding area around the tumor site is declared free of tumor. The major appeal of the Mohs procedure is comprehensive margin assessment in one surgical session. Unlike with elliptical excisions, where only representative perpendicular sections to the margins are microscopically examined, if done right, en face sections of the entire periphery of the tissue surrounding a tumor bed are examined during Mohs surgery. The procedure works well for basal cell and squamous cell carcinomas of the head and neck area, likely resulting in better cosmetic outcomes than with conventional surgery. However, we caution against the use
401
of Mohs surgery for the treatment of melanoma. The main problem with Mohs surgery is its reliance on frozen section for microscopic analysis. It is well documented that the histopathologic diagnosis of melanoma (in situ and/or invasive) is more difficult and therefore more likely associated with diagnostic errors using frozen compared to permanent sections.9 On the other hand, some skilled laboratories can produce high-quality frozen sections. To overcome the quality disadvantage related to frozen sections, rapid immunohistochemical staining protocols, such as using antibodies to Melan-A/MART1, have been developed and incorporated into the practice of Mohs surgery of melanomas.10 However, due to limitations in the sensitivity IHC markers (some melanomas, in particular desmoplastic melanomas, are negative for Melan-A/MART1), there is risk for failure to recognize invasive melanoma. Likewise, the extent of some lentigo maligna (melanoma in situ) lesions may be overestimated, if the surgeon relies heavily on IHC for Melan-A/MART1, due to false-positive labeling. Another disadvantage related to the practice of Mohs surgery for melanoma is the fact that detailed examination of the main tumor debulk for invasive melanoma is not necessarily routine and difficult to accomplish or imprecise if only frozen sections are used. Permanent sections, often in combination with immunohistochemical studies, are best for an accurate assessment of tumor staging. This disadvantage can easily be overcome if the Mohs surgeon saves the tumor debulk and submits it to a dermatopathologist for further examination by permanent sections.8,11–13 It should be standard practice that every tissue of a melanoma excision is thoroughly examined for possible invasive melanoma irrespective of whether the excision was part of a Mohs procedure. If invasive melanoma is found, features relevant for prognosis/ tumor staging need to be clearly recorded as required for any other surgical excision for melanoma.
Staged Excision Fig. 33.7 Histopathology of the excision of a pT3a nodular melanoma. The tumor is sharply demarcated and surrounded by a wide rim of normal tissue.
A staged excision, sometimes also referred to as “slow Mohs,” follows the principle of comprehensive margin assessment. However, instead of frozen sections rapidly processed and stained (rush), permanent
B
A
C
Fig. 33.8 Conventional Elliptical Skin Excision of a Melanoma. (A) Unoriented skin ellipse with melanoma in the center, surrounded by grossly normal skin. (B) The periphery of the skin and the underlying subcutis are inked. (C) Serial slices are taken perpendicular to the longitudinal axis of the ellipse from one pole to the other.
402
SECTION VII Margin Assessment of Melanomas
A
C
B
D Fig. 33.9 Mohs Surgery for Melanoma In Situ. (A) Clinical lesion of lentigo maligna melanoma in situ. (B) Removal of the clinically visible tumor (debulk). (C) Marking of additional 5 mm rim of clinically normal tissue. (D) Removal of tissue peripheral and underneath the tumor, which is to be examined by frozen sections. (Courtesy Dr. Brad Merritt.)
sections are examined. Tumor debulk is removed and carefully examined for the presence or absence of in situ and/or invasive melanoma. Separate tissue sections are examined for margin assessment. If melanoma is found in one of the margin sections, an additional or multiple layers are obtained as necessary until no more tumor is seen. There are multiple variations of this procedure.8,13,14 The margin may be assessed and mapped first as in the “square” technique before the center of the tumor is removed and examined.13,14 Alternatively, the debulk and an initial rim of tissue may be removed in one surgical session, with a possible second or third surgical session, if the margins are positive.8,12 The margins may be examined as layers en face as traditionally done during the Mohs procedure thereby permitting “comprehensive” margin assessment, or they may be examined in a section plane perpendicular to the outer rim and center of the clinical lesion. The en face margin approach has the theoretical advantage of sampling a contiguous layer of tissue around the tumor, but it is not free of pitfalls. A large margin section may be difficult to process or it may be difficult to precisely pinpoint a focus of tumor. Furthermore, while the margin assessment by en face sections works well for contiguous solid tumors, it is subject to sampling errors for tumors with noncontiguous tumor growth, such as melanoma in situ within the epidermis, where areas of epidermis involved by melanoma cells may alternate
with areas that look normal (“skip areas”). Most importantly, however, it may be difficult to interpret the significance of subtle findings, i.e., to be certain whether or not a low-density junctional melanocytic proliferation represents the trailing edge of a lentigo maligna or background solar melanocyte hyperplasia. This distinction is much more easily made on sections perpendicular to the center and periphery of a lesion. Perpendicular sections permit comparing the features (cell density, growth pattern, cytology) of the melanoma (usually in situ) with the most peripheral tissue. If there has been a clear drop in cell density of junctional melanocytes and/or change to blander cytology, one can be more confident about the territory of the melanoma versus normal surrounding sun-damaged skin. This diagnostic advantage is the main reason why we prefer sections for histopathologic margin analysis when they were taken perpendicular to the center of the lesion and specimen periphery. For practical reasons, this means that only representative sections are examined. Serial perpendicular sections of the entire tissue would be too time consuming and costly. However, we have not found a major discrepancy in the margin assessment within a 2- to 3-mm-thick section of tissue. A margin clearance of 3 mm usually means that the true margin of the tissue piece is negative. While there may be fluctuations in the peripheral clearance or the risk of skip areas, those rarely exceed 3 mm in horizontal
CHAPTER 33 Margin Assessment of Cutaneous Melanoma dimension, which is why in our experience a 3-mm clearance on a representative perpendicular section of a melanoma in situ has proven to be a reliable distance for a surgically negative margin in most cases. There is not one right way to map an area of melanoma in situ and to excise it successfully with a negative margin of normal skin. What matters is that whichever method of surgical removal (Mohs vs. conventional surgery; staged excision with en face or perpendicular sections) is chosen, that it be subject to quality assurance metrics, and a rate of local recurrence/persistence of melanoma in situ is achieved that falls below 5% over a time period of 5 years, taking into account that adjustments may need to be made for the complexity of surgical task at hand (e.g., more difficult, if the melanoma in situ involves eyelid and the conjunctiva, or if there has already been a local recurrence after prior surgery and reconstruction, in which case procedures to map the tumor territory are less a curate). Furthermore, even with unequivocal negative margins and the most careful margin assessment, some melanomas, in particular lentigo maligna and acral melanoma lesions, may develop in the same area due to a field effect. Two ways of tissue processing, which are commonly used at Memorial Sloan Kettering Cancer Center, are illustrated herein. In our hands they work well for margin assessment of melanoma in situ or thin melanomas. In one method (Fig. 33.10) the debulk is removed and separate rims of additional peripheral margins are obtained and oriented in clockwise fashion. The tissue is carefully sectioned so that the orientation is maintained and thin slides of tumor tissue can be analyzed for in situ and/or invasive melanoma. With sections taken in a perpendicular orientation to the center and outer side margin, it is usually straightforward to judge the periphery of the melanoma and measure the margin clearance. In a different approach (Fig. 33.11), a saucerization procedure is performed first containing the clinically visible lesion and a thin rim of normal tissue. The specimen is carefully examined for the presence or absence of in situ and invasive melanoma and the margin status. Depending on whether or not in situ melanoma is at or close to the margin and whether or not any invasive tumor was found, an additional rim of normal tissue peripheral and deep to the initial saucerization procedure is taken to ensure complete removal of the neoplasm.
PITFALLS IN MARGIN ASSESSMENT The assessment of a margin is usually straightforward, but can be problematic. The pathologist reviewing slides to determine the margin
403
status of a surgical tumor excision depends on accurate grossing and documentation of the findings via gross description and/or photography, especially when an excision is oriented and a positive margin needs to be specified precisely. An error in the gross description or inconsistency between the description and what was done at the grossing station may lead to a false margin assessment. Margin mapping is especially challenging after prior reconstructive surgery. The accuracy of the margin status also depends on how extensively or representatively margins were sampled in the histology laboratory, whether ink was applied carefully or was let to run onto tissue surfaces, which do not correspond to a true surgical margin, and whether tissue sections were correctly embedded to permit assessment of margins. For example, wrongly embedded sections from a side margin lacking epidermis at the edge preclude adequate assessment of the side margin status of a melanoma in situ. Cautery or dry artifacts may also compromise margin evaluation. However, even under technically optimal conditions, there is risk for interpretative errors. A low cell density trailing edge of a lentigo maligna may falsely be judged as “background” and wrongly declared a negative margin. On the other hand, a melanocytic proliferation may erroneously be interpreted as part of a melanoma when in fact it represents a separate lesion, such as an incidental nevus or lentigo in the vicinity of or colliding with a melanoma. The best protection against the latter pitfall is correlation of the histopathologic with the clinical findings (Fig. 33.12). A clinical picture can be invaluable.
MARGIN REPORTING When a melanoma is excised, the margin status needs to be documented as either involved (positive) or uninvolved (negative) by melanoma. If the margin is positive, it should be stated whether it is involved by melanoma in situ and/or invasive melanoma.15 If possible, that is, when a specimen was oriented, the precise area of the specimen, which has a positive margin, should be indicated, so that a more targeted and limited re-excision can be performed, if feasible. When the margins are clearly negative, it usually suffices to say so. We do not recommend routine measurements of the distance of the periphery of every melanoma to the nearest side or deep margin, unless the margin clearance is narrow and there is risk for histologic sampling error (Table 33.2). When a “narrow” margin is “too narrow” depends on the type of melanoma. For the majority of melanomas, a narrow margin will refer to the distance of melanoma in situ from the
TABLE 33.2 Margin Reporting Histopathologic Margin Assessment
Reporting Suggestion
Melanoma in situ extends to a side margin
Melanoma in situ extends to a side margin • specify, which margin is positive, if possible Melanoma in situ extends to within <3 mm of a side margin • specify, which margin is narrow, if possible The margins are not involved • the margin clearance does not need to be further specified Invasive melanoma extends to a side margin • specify precisely, where the margin is positive, if possible Invasive melanoma extends to the deep margin • specify precisely, where the margin is positive, if possible Invasive melanoma extends to within …(mm) of a side margin • specify precisely, where the margin is narrow, if possible Invasive melanoma extends to within …(mm) of a deep margin • specify precisely, where the margin is narrow, if possible The margins are not involved by melanoma • no further details are necessary, if the margin clearance is 3 mm or more
Melanoma in situ extends to within <3 mm of a side margin The clearance between melanoma in situ and the nearest side margin is >3 mm Invasive melanoma extends to a side margin Invasive melanoma extends to the deep margin Invasive melanoma extends close to a side margin Invasive melanoma extends close to the deep margin Invasive melanoma is not close to the side or deep margin
404
SECTION VII Margin Assessment of Melanomas
A B
C
D
E
F Fig. 33.10 Staged Excision—Method 1. (A) Clinical lesion and markings for excision of tumor debulk and surrounding quarters (12–3, 3–6, 6–9, and 9–12 o’clock) (image courtesy Dr. KS Nehal.) (B) Each peripheral quarter is marked with a suture to indicate 12, 3, 6, and 9 o’clock, respectively. (C) Each piece (debulk and sections corresponding to a quarterly hour) are placed in a separate container. (D) Each peripheral quarter and the debulk are serially cut into smaller tissue slices. (E) Each tissue section is placed in a designated cassette. (F) Sections from each block are examined for tumor diagnosis and margin assessment.
405
CHAPTER 33 Margin Assessment of Cutaneous Melanoma
A
B
C
E
D
F Fig. 33.11 Stage Excision—Method 2. (A) Clinical lesion. (B) Wound after shave removal of the clinically visible lesion. (C) Histopathology of the shave excision (scanning magnification). (D) The shave excision shows melanoma in situ. (E) Subsequent re-excision with a rim of normal skin and subcutis. (F) The skin surrounding the surgical wound is benign and free of melanoma.
Nevus 1
Site of prior lesion
B
A Fig. 33.12 (A) Clinical image of melanoma biopsy site with nearby nevi. A surgical excision along the lines of the ellipse would cut through the nevi 1 and 2. (B) Histopathology of the excision shows a scar. There is no residual tumor. The melanocytes highlighted by the immunostain for melan-A are not part of the previously biopsied lesion, but correspond to the clinically distinct separate melanocytic nevi.
Nevus 2
406
SECTION VII Margin Assessment of Melanomas
Fig. 33.13 Excision of a melanoma of the ear with wide clearance (H&E and IHC for melan-A). It is readily apparent that the margins are negative and adequate. It suffices to report that the margins are not involved by melanoma. It would be difficult to precisely measure the distance of the melanoma from the nearest side margin, and that effort would be of no added clinical value.
nearest side margin. A sharply demarcated small superficial spreading or nevoid melanoma is likely adequately excised with a histopathologically measured rim of normal tissue of 2 mm. An ill-defined lentigo maligna melanoma in situ with skip areas often needs in our experience a rim of 3 mm or more of normal tissue to ensure adequate clearance. Based on our experience with lentigo maligna melanoma in situ (clinical experience with review of cases, which locally persisted/recurred as well as step-sectioning tissue samples of margin with tumor present, but away from the margin), a 3-mm clearance of a 2- to 3-mm-thick slice of tissue usually means that the margin is truly negative and that the risk for histologic sampling error is extremely low. This is in keeping with published observations.16 Accordingly, a recurrence of a lentigo maligna melanoma in situ related to a false-negative margin report is unlikely if the histopathologic clearance was 3 mm or more. If the clearance of a melanoma in situ from the nearest side margin is greater than 3 mm, documenting this clearance may be helpful, but it usually suffices to declare the margin as “negative” or “not involved.” We do not believe that it is necessary to precisely measure obvious wide clearances (Fig. 33.13). For the majority of melanomas (in situ, of invasive to tumor stage pT3 or less) located on the trunk of proximal extremities, the deep margin is usually negative. A full-thickness excision with subcutis should establish sufficient clearance with depth. Accordingly, we do not see any value in an extra effort of measuring the distance of a Clark II or III melanoma to the nearest deep subcutaneous margin. By definition, Clark II or III melanomas are confined to the papillary dermis, and it should be obvious to the surgeon that if deep dermal and subcutaneous tissue was removed, and the margin was reported as negative, the margin clearance should be sufficient. For invasive melanoma, especially those located in the head and neck region, where there are greater limitations to how wide and deep
an excision can be performed, or if the tumor displays neurotropism, the clearance from the deep margin may be a problem, and a narrow margin clearance should be documented in the pathology report to alert the clinician to a higher risk for local recurrence and potential considerations for additional surgical clearance or postoperative radiation treatment. There is limited data on the minimum clearance of invasive melanoma from the nearest deep margin. Based on our experience, if invasive melanoma, especially spindle cell desmoplastic and/or neurotropic melanoma, extends to within less than 3 mm of the deep margin, we recommend documenting this finding and specifying, if possible, where the tumor extends close to the deep margin. With the advances in digital imaging, we envision future pathology reports that will use an image of the tumor to document its relationship to side and deep margins. The image has the added advantage of not only allowing assessment of the margin clearance, if that is wanted, but also conveying information about the anatomic levels involved, the volume, and the growth pattern of the tumor. For a nodular, relatively circumscribed tumor a narrower margin clearance is more likely sufficient to minimize risk for local recurrence, while a wide safety margin is necessary for a diffusely infiltrative tumor.
REFERENCES 1. www.aad.org/practicecenter/quality/clinical-guidelines/melanoma/ surgical-management. 2. www.nccn.org. 3. www.skincancer.org. 4. Thomas JM, et al. Excision margins in high-risk malignant melanoma. N Engl J Med. 2004;350:757–766. 5. Veronesi U, et al. Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm. N Engl J Med. 1988;318:1159–1162. Erratum in: N Engl J Med 1991 Jul 25;325:292. 6. Doepker MP, et al. Is a wider margin (2 cm vs. 1 cm) for a 1.01-2.0 mm melanoma necessary? Ann Surg Oncol. 2016;23:2336–2342. 7. Kunishige JH, Brodland DG, Zitelli JA. Surgical margins for melanoma in situ. J Am Acad Dermatol. 2012;66:438–444. 8. Hazan C, et al. Staged excision for lentigo maligna and lentigo maligna melanoma: a retrospective analysis of 117 cases. J Am Acad Dermatol. 2008;58:142–148. 9. Prieto VG, et al. Are en face frozen sections accurate for diagnosing margin status in melanocytic lesions? Am J Clin Pathol. 2003;120:203–208. 10. Valentín-Nogueras SM, et al. Mohs micrographic surgery using MART-1 immunostain in the treatment of invasive melanoma and melanoma in situ. Dermatol Surg. 2016;42:733–744. 11. Iorizzo LJ 3rd, et al. Importance of vertical pathology of debulking specimens during Mohs micrographic surgery for lentigo maligna and melanoma in situ. Dermatol Surg. 2013;39(3 Pt 1):365–371. 12. Connolly KL, et al. Locally recurrent lentigo maligna and lentigo maligna melanoma: characteristics and time to recurrence after surgery. Dermatol Surg. 2017;43:792–797. 13. Johnson TM, et al. Usefulness of the staged excision for lentigo maligna and lentigo maligna melanoma: the “square” procedure. J Am Acad Dermatol. 1997;37:758–763. 14. Moyer JS, et al. Efficacy of staged excision with permanent section margin control for cutaneous head and neck melanoma. JAMA Dermatol. 2017;153:282–288. 15. Smoller B, et al. Protocol for the examination of specimens from patients with melanoma of the skin. www.cap.org/cancerprotocols. 16. Joyce KM, et al. An assessment of histological margins and recurrence of melanoma in situ. Plast Reconstr Surg Glob Open. 2015;3:e301.
OUTLINE Guidelines for Melanoma Margins, 398 Tissue Processing and Margin Review, 399 Conventional Elliptical Excisions, 400 Mohs Surgery, 401 Staged Excision, 401
Pitfalls in Margin Assessment, 403 Margin Reporting, 403
Once a diagnosis of primary cutaneous melanoma has been established by a pathologist, the treatment of choice is usually complete removal by surgical excision. Surgery is to accomplish two goals: (a) to permit complete assessment of the entire tumor for prognostic purposes and (b) to minimize risk for metastasis. For in situ melanomas complete surgical removal is curative. If the primary melanoma is confined to the epidermis (in situ) and has implicitly not yet invaded dermis and vascular structures, there should be no risk for distant recurrence. There are cases of reported melanoma in situ and subsequent recurrence due to occult invasion, but the diagnosis of melanoma in situ was simply incorrect. Invasion had occurred but was not detected due to insufficient histopathologic sampling, regression, or interpretative errors. Surgery may also be curative for some lesions of invasive melanoma. The probability of curative surgery is higher for tumors with prognostically favorable (e.g., thickness < 0.5 mm, no mitosis, no ulceration) than unfavorable features. When the prognosis is known to be unfavorable (e.g., detection of lymphatic invasion on biopsy), or even when metastatic spread is already evident clinically (e.g., visible in-transit metastasis, palpable lymph node metastasis), there is still a rationale for surgical excision. Removing a high-risk primary melanoma or tumor already known to have metastasized makes sense because the primary tumor continues to pose a threat for spreading tumor cells to distant sites and/ or local tissue damage (ulceration and invasion of deep tissue structures, with risk for infection, nerve or vascular injury with pain, bleeding, or loss of function).
Guidelines have been proposed for surgical margins based on historic practice, some published data on the subject, and consensus among clinicians selected to serve on panels.1–3 These guidelines have varied over the years. There has been a general trend toward narrower margins for melanoma as it has become apparent, for example, that wide excisions with 5-cm margins for invasive melanoma do not offer any advantage over a 1- or 2-cm margin for survival or risk for local recurrence.4,5 Furthermore, for 1- to 2-mm thick primary melanomas, a 1-cm margin often seems to suffice.6 On the other hand, for melanoma in situ it has also become apparent that some lesions, in particular lentigo malignas, not uncommonly require a 7- to 10-mm or occasionally even wider clinical margin for successful clearance (Table 33.1).7,8 With regard to guidelines, a few comments are in order. First, the margin metrics reflect clinical (Figs. 33.1 and 33.2), not histopathologic, measurements (Fig. 33.3). Second, the purpose of the guidelines of clinical margins is to suggest a rim of tissue for a given melanoma thickness that will achieve a final histopathologically confirmed negative margin at a high probability. It is not the goal or clinically necessary that the tumor be surrounded by a clearance of 5 mm or more of pathologically confirmed normal tissue. For example, when a melanoma in situ has been excised with a clinical measurement of 5 mm and there is a rim of normal skin throughout the periphery of the excision specimen, the surgical margin should be classified as negative and adequate, even if the histopathologic clearance is less than 5 mm, which is often the case, especially when residual melanoma in situ is present (Fig. 33.4). The purpose of the guidelines is that following them will often yield a negative margin (Fig. 33.5). Sometimes, however, there is such a broad subclinical extent that the margin is unexpectedly positive or too narrow (Fig. 33.6). If the clinical goal was to remove the tumor with a negative margin, and additional tissue can be taken with limited or no extra morbidity to the patient, an additional surgical procedure is then in order to achieve that goal. Not uncommonly, following the margin guidelines will yield an unnecessarily wide clearance, and in retrospect one wonders whether a smaller excision would not have sufficed (Fig. 33.7). Second, guidelines are guidelines, not mandates. They apply to most but not all lesions or clinical and personal circumstances. Compromises
GUIDELINES FOR MELANOMA MARGINS When the goal is to remove a primary melanoma surgically, the question arises how widely around the clinically visible lesion or biopsy site should the excision margin be drawn to ensure complete removal of the tumor (in practical terms a histopathologically confirmed negative margin). For some melanomas (e.g., discrete pigmented lesion) there is a good correlation between the clinical and microscopic margin assessment. For other melanomas, however, there is subclinical (clinically invisible or poorly visible, but microscopically confirmed) extension of the tumor in the horizontal plane beyond the area of skin clinically thought to represent melanoma.
398
CHAPTER 33 Margin Assessment of Cutaneous Melanoma
Keywords margin reporting guidelines Mohs staged excision
398.e1
CHAPTER 33 Margin Assessment of Cutaneous Melanoma
399
may need to be made to balance the goal of a negative margin with the goal of minimizing morbidity and maximizing quality of life.
TISSUE PROCESSING AND MARGIN REVIEW Whether or not a melanoma has been entirely removed is assessed by microscopic review of an excision specimen. A margin is determined negative if there is only normal tissue and no tumor seen at the outermost rim of the surgical excision specimen (side and deep margin in a twodimensional view). The accuracy of the margin assessment depends on adequate orientation, processing, and competent microscopic review of the tissue.
TABLE 33.1 AAD Endorsed Margin
Recommendations for Melanoma Tumor Thickness
Margin
Melanoma in situ Melanoma ≤1 mm in thickness Melanoma >1 mm and <2 mm in thickness Melanoma >2 mm in thickness
5–10 mm 1 cm 1–2 cm 2 cm
Fig. 33.1 Clinical measurement of a 5-mm margin for surgical excision of a previously biopsied and diagnosed melanoma in situ. (Courtesy Dr. Erica Lee.)
AAD, American Academy of Dermatology.
A
B
C
D Fig. 33.2 Clinical measurement of a 2-cm margin for a surgical excision of a pT3b melanoma. (A) Prior biopsy site. (B) Longitudinal axis of elliptical excision. (C) Measuring 2-cm distance from biopsy site for side margin. (D) Marking of the ellipse of skin to be excised. (Courtesy Dr. Daniel Coit.)
400
SECTION VII Margin Assessment of Melanomas
Conventional Elliptical Excisions
Fig. 33.3 Histopathologic measurement of margin clearance. Note the difference in cell density between melanoma in situ and normal surrounding skin.
Fig. 33.4 Residual melanoma at the site of a scar (melanocytes are seen in red–IHC for melan-A). The nearest distance of the edge of the melanoma in situ to the nearest side margin measures (measure microscopically) is 3.5 mm.
Fig. 33.5 Histopathology of the excision of a pT2a superficial spreading melanoma with a negative margin. The melanoma is surrounded by a rim of histopathologically confirmed normal skin.
The majority of surgical excisions are elliptical specimens (Fig. 33.8). Typically tissue slides are taken perpendicular to the longitudinal plane of the ellipse, in serial intervals from one end of the ellipse to the other. For precise margin mapping, the specimen should be oriented. This can be accomplished by attaching stitches or other marks (ink) to the specimen (e.g., long stitch indicating the 12 o’clock margin). A corresponding image (digital or print) of the clinical lesion and gross specimen is helpful to avoid misorientation. Often specimens are oriented in a clockwise fashion, so that a microscopically confirmed positive margin can be precisely identified (e.g., positive 3 o’clock margin). If the specimen is received in the pathology laboratory with orientation marks, it should be inked, best in at least two colors identifying the two different sides of an elliptical excision (e.g., medial vs. lateral or 3 o’clock vs. 9 o’clock). The gross description should clearly specify what color ink is used for which margin, such as “the margin is inked black from 12 to 6 o’clock along 3 o’clock and inked blue from 6 to 12 o’clock along 9 o’clock.” Excisional biopsies or small excisions should be submitted entirely for histopathologic margin assessment. Small excisions are usually serially sectioned (“bread-loafed”) from one end (usually the tip of the elliptically shaped specimen surface) to the other with a sectioning knife or sharp blade held perpendicular to the side margins. For large excisions, especially for re-excisions with a previously negative albeit narrow margin, it is not necessary to submit all the tissue for processing. One may focus the tissue sampling on the area most likely to be positive (e.g., grossly visible lesion near a margin or skin surrounding the prior surgical site). Assessing the margins of a melanoma by conventional elliptical excision is fairly accurate and works well in most cases of clinically visible pigmented lesions. With serial bread-loaf sections taken perpendicular to the side and deep margin, one can readily assess the relationship of the tumor to side and deep margins and assess the clearance. Positive margins are uncommon and usually related to unexpected subclinical extension of the tumor or suboptimal surgical technique. False-negative margins (margin status reported as negative,
A
B Fig. 33.6 Histopathology of the excision of a pT2a superficial spreading melanoma. (A) In spite of a clinical measurement of a 1-cm margin, subclinical (clinically not visible) melanoma in situ extends to a side margin. (B) Although the melanoma in situ is not directly transected at the peripheral side margin in this section, it extends so close to the side margin that the margin status should not be reported as negative. It should be regarded as most likely positive.
CHAPTER 33 Margin Assessment of Cutaneous Melanoma but residual tumor persists, continues to grow and locally recurs) are rare. They may be related to suboptimal grossing, embedding, or sectioning and related failure to sample the positive margin, or failure of the pathologist to adequately recognize a histopathologically subtle positive margin.
Mohs Surgery Mohs surgery has been advocated as a surgical excision method for comprehensive margin assessment.7 Intraoperatively, the dermatologic surgeon takes en face layers of tissue around the entire tumor and microscopically assesses for the presence or absence of tumor using frozen sections (Fig. 33.9). If a layer contains tumor, an additional layer is taken. If no tumor is seen, the corresponding area around the tumor site is declared free of tumor. The major appeal of the Mohs procedure is comprehensive margin assessment in one surgical session. Unlike with elliptical excisions, where only representative perpendicular sections to the margins are microscopically examined, if done right, en face sections of the entire periphery of the tissue surrounding a tumor bed are examined during Mohs surgery. The procedure works well for basal cell and squamous cell carcinomas of the head and neck area, likely resulting in better cosmetic outcomes than with conventional surgery. However, we caution against the use
401
of Mohs surgery for the treatment of melanoma. The main problem with Mohs surgery is its reliance on frozen section for microscopic analysis. It is well documented that the histopathologic diagnosis of melanoma (in situ and/or invasive) is more difficult and therefore more likely associated with diagnostic errors using frozen compared to permanent sections.9 On the other hand, some skilled laboratories can produce high-quality frozen sections. To overcome the quality disadvantage related to frozen sections, rapid immunohistochemical staining protocols, such as using antibodies to Melan-A/MART1, have been developed and incorporated into the practice of Mohs surgery of melanomas.10 However, due to limitations in the sensitivity IHC markers (some melanomas, in particular desmoplastic melanomas, are negative for Melan-A/MART1), there is risk for failure to recognize invasive melanoma. Likewise, the extent of some lentigo maligna (melanoma in situ) lesions may be overestimated, if the surgeon relies heavily on IHC for Melan-A/MART1, due to false-positive labeling. Another disadvantage related to the practice of Mohs surgery for melanoma is the fact that detailed examination of the main tumor debulk for invasive melanoma is not necessarily routine and difficult to accomplish or imprecise if only frozen sections are used. Permanent sections, often in combination with immunohistochemical studies, are best for an accurate assessment of tumor staging. This disadvantage can easily be overcome if the Mohs surgeon saves the tumor debulk and submits it to a dermatopathologist for further examination by permanent sections.8,11–13 It should be standard practice that every tissue of a melanoma excision is thoroughly examined for possible invasive melanoma irrespective of whether the excision was part of a Mohs procedure. If invasive melanoma is found, features relevant for prognosis/ tumor staging need to be clearly recorded as required for any other surgical excision for melanoma.
Staged Excision Fig. 33.7 Histopathology of the excision of a pT3a nodular melanoma. The tumor is sharply demarcated and surrounded by a wide rim of normal tissue.
A staged excision, sometimes also referred to as “slow Mohs,” follows the principle of comprehensive margin assessment. However, instead of frozen sections rapidly processed and stained (rush), permanent
B
A
C
Fig. 33.8 Conventional Elliptical Skin Excision of a Melanoma. (A) Unoriented skin ellipse with melanoma in the center, surrounded by grossly normal skin. (B) The periphery of the skin and the underlying subcutis are inked. (C) Serial slices are taken perpendicular to the longitudinal axis of the ellipse from one pole to the other.
402
SECTION VII Margin Assessment of Melanomas
A
C
B
D Fig. 33.9 Mohs Surgery for Melanoma In Situ. (A) Clinical lesion of lentigo maligna melanoma in situ. (B) Removal of the clinically visible tumor (debulk). (C) Marking of additional 5 mm rim of clinically normal tissue. (D) Removal of tissue peripheral and underneath the tumor, which is to be examined by frozen sections. (Courtesy Dr. Brad Merritt.)
sections are examined. Tumor debulk is removed and carefully examined for the presence or absence of in situ and/or invasive melanoma. Separate tissue sections are examined for margin assessment. If melanoma is found in one of the margin sections, an additional or multiple layers are obtained as necessary until no more tumor is seen. There are multiple variations of this procedure.8,13,14 The margin may be assessed and mapped first as in the “square” technique before the center of the tumor is removed and examined.13,14 Alternatively, the debulk and an initial rim of tissue may be removed in one surgical session, with a possible second or third surgical session, if the margins are positive.8,12 The margins may be examined as layers en face as traditionally done during the Mohs procedure thereby permitting “comprehensive” margin assessment, or they may be examined in a section plane perpendicular to the outer rim and center of the clinical lesion. The en face margin approach has the theoretical advantage of sampling a contiguous layer of tissue around the tumor, but it is not free of pitfalls. A large margin section may be difficult to process or it may be difficult to precisely pinpoint a focus of tumor. Furthermore, while the margin assessment by en face sections works well for contiguous solid tumors, it is subject to sampling errors for tumors with noncontiguous tumor growth, such as melanoma in situ within the epidermis, where areas of epidermis involved by melanoma cells may alternate
with areas that look normal (“skip areas”). Most importantly, however, it may be difficult to interpret the significance of subtle findings, i.e., to be certain whether or not a low-density junctional melanocytic proliferation represents the trailing edge of a lentigo maligna or background solar melanocyte hyperplasia. This distinction is much more easily made on sections perpendicular to the center and periphery of a lesion. Perpendicular sections permit comparing the features (cell density, growth pattern, cytology) of the melanoma (usually in situ) with the most peripheral tissue. If there has been a clear drop in cell density of junctional melanocytes and/or change to blander cytology, one can be more confident about the territory of the melanoma versus normal surrounding sun-damaged skin. This diagnostic advantage is the main reason why we prefer sections for histopathologic margin analysis when they were taken perpendicular to the center of the lesion and specimen periphery. For practical reasons, this means that only representative sections are examined. Serial perpendicular sections of the entire tissue would be too time consuming and costly. However, we have not found a major discrepancy in the margin assessment within a 2- to 3-mm-thick section of tissue. A margin clearance of 3 mm usually means that the true margin of the tissue piece is negative. While there may be fluctuations in the peripheral clearance or the risk of skip areas, those rarely exceed 3 mm in horizontal
CHAPTER 33 Margin Assessment of Cutaneous Melanoma dimension, which is why in our experience a 3-mm clearance on a representative perpendicular section of a melanoma in situ has proven to be a reliable distance for a surgically negative margin in most cases. There is not one right way to map an area of melanoma in situ and to excise it successfully with a negative margin of normal skin. What matters is that whichever method of surgical removal (Mohs vs. conventional surgery; staged excision with en face or perpendicular sections) is chosen, that it be subject to quality assurance metrics, and a rate of local recurrence/persistence of melanoma in situ is achieved that falls below 5% over a time period of 5 years, taking into account that adjustments may need to be made for the complexity of surgical task at hand (e.g., more difficult, if the melanoma in situ involves eyelid and the conjunctiva, or if there has already been a local recurrence after prior surgery and reconstruction, in which case procedures to map the tumor territory are less a curate). Furthermore, even with unequivocal negative margins and the most careful margin assessment, some melanomas, in particular lentigo maligna and acral melanoma lesions, may develop in the same area due to a field effect. Two ways of tissue processing, which are commonly used at Memorial Sloan Kettering Cancer Center, are illustrated herein. In our hands they work well for margin assessment of melanoma in situ or thin melanomas. In one method (Fig. 33.10) the debulk is removed and separate rims of additional peripheral margins are obtained and oriented in clockwise fashion. The tissue is carefully sectioned so that the orientation is maintained and thin slides of tumor tissue can be analyzed for in situ and/or invasive melanoma. With sections taken in a perpendicular orientation to the center and outer side margin, it is usually straightforward to judge the periphery of the melanoma and measure the margin clearance. In a different approach (Fig. 33.11), a saucerization procedure is performed first containing the clinically visible lesion and a thin rim of normal tissue. The specimen is carefully examined for the presence or absence of in situ and invasive melanoma and the margin status. Depending on whether or not in situ melanoma is at or close to the margin and whether or not any invasive tumor was found, an additional rim of normal tissue peripheral and deep to the initial saucerization procedure is taken to ensure complete removal of the neoplasm.
PITFALLS IN MARGIN ASSESSMENT The assessment of a margin is usually straightforward, but can be problematic. The pathologist reviewing slides to determine the margin
403
status of a surgical tumor excision depends on accurate grossing and documentation of the findings via gross description and/or photography, especially when an excision is oriented and a positive margin needs to be specified precisely. An error in the gross description or inconsistency between the description and what was done at the grossing station may lead to a false margin assessment. Margin mapping is especially challenging after prior reconstructive surgery. The accuracy of the margin status also depends on how extensively or representatively margins were sampled in the histology laboratory, whether ink was applied carefully or was let to run onto tissue surfaces, which do not correspond to a true surgical margin, and whether tissue sections were correctly embedded to permit assessment of margins. For example, wrongly embedded sections from a side margin lacking epidermis at the edge preclude adequate assessment of the side margin status of a melanoma in situ. Cautery or dry artifacts may also compromise margin evaluation. However, even under technically optimal conditions, there is risk for interpretative errors. A low cell density trailing edge of a lentigo maligna may falsely be judged as “background” and wrongly declared a negative margin. On the other hand, a melanocytic proliferation may erroneously be interpreted as part of a melanoma when in fact it represents a separate lesion, such as an incidental nevus or lentigo in the vicinity of or colliding with a melanoma. The best protection against the latter pitfall is correlation of the histopathologic with the clinical findings (Fig. 33.12). A clinical picture can be invaluable.
MARGIN REPORTING When a melanoma is excised, the margin status needs to be documented as either involved (positive) or uninvolved (negative) by melanoma. If the margin is positive, it should be stated whether it is involved by melanoma in situ and/or invasive melanoma.15 If possible, that is, when a specimen was oriented, the precise area of the specimen, which has a positive margin, should be indicated, so that a more targeted and limited re-excision can be performed, if feasible. When the margins are clearly negative, it usually suffices to say so. We do not recommend routine measurements of the distance of the periphery of every melanoma to the nearest side or deep margin, unless the margin clearance is narrow and there is risk for histologic sampling error (Table 33.2). When a “narrow” margin is “too narrow” depends on the type of melanoma. For the majority of melanomas, a narrow margin will refer to the distance of melanoma in situ from the
TABLE 33.2 Margin Reporting Histopathologic Margin Assessment
Reporting Suggestion
Melanoma in situ extends to a side margin
Melanoma in situ extends to a side margin • specify, which margin is positive, if possible Melanoma in situ extends to within <3 mm of a side margin • specify, which margin is narrow, if possible The margins are not involved • the margin clearance does not need to be further specified Invasive melanoma extends to a side margin • specify precisely, where the margin is positive, if possible Invasive melanoma extends to the deep margin • specify precisely, where the margin is positive, if possible Invasive melanoma extends to within …(mm) of a side margin • specify precisely, where the margin is narrow, if possible Invasive melanoma extends to within …(mm) of a deep margin • specify precisely, where the margin is narrow, if possible The margins are not involved by melanoma • no further details are necessary, if the margin clearance is 3 mm or more
Melanoma in situ extends to within <3 mm of a side margin The clearance between melanoma in situ and the nearest side margin is >3 mm Invasive melanoma extends to a side margin Invasive melanoma extends to the deep margin Invasive melanoma extends close to a side margin Invasive melanoma extends close to the deep margin Invasive melanoma is not close to the side or deep margin
404
SECTION VII Margin Assessment of Melanomas
A B
C
D
E
F Fig. 33.10 Staged Excision—Method 1. (A) Clinical lesion and markings for excision of tumor debulk and surrounding quarters (12–3, 3–6, 6–9, and 9–12 o’clock) (image courtesy Dr. KS Nehal.) (B) Each peripheral quarter is marked with a suture to indicate 12, 3, 6, and 9 o’clock, respectively. (C) Each piece (debulk and sections corresponding to a quarterly hour) are placed in a separate container. (D) Each peripheral quarter and the debulk are serially cut into smaller tissue slices. (E) Each tissue section is placed in a designated cassette. (F) Sections from each block are examined for tumor diagnosis and margin assessment.
405
CHAPTER 33 Margin Assessment of Cutaneous Melanoma
A
B
C
E
D
F Fig. 33.11 Stage Excision—Method 2. (A) Clinical lesion. (B) Wound after shave removal of the clinically visible lesion. (C) Histopathology of the shave excision (scanning magnification). (D) The shave excision shows melanoma in situ. (E) Subsequent re-excision with a rim of normal skin and subcutis. (F) The skin surrounding the surgical wound is benign and free of melanoma.
Nevus 1
Site of prior lesion
B
A Fig. 33.12 (A) Clinical image of melanoma biopsy site with nearby nevi. A surgical excision along the lines of the ellipse would cut through the nevi 1 and 2. (B) Histopathology of the excision shows a scar. There is no residual tumor. The melanocytes highlighted by the immunostain for melan-A are not part of the previously biopsied lesion, but correspond to the clinically distinct separate melanocytic nevi.
Nevus 2
406
SECTION VII Margin Assessment of Melanomas
Fig. 33.13 Excision of a melanoma of the ear with wide clearance (H&E and IHC for melan-A). It is readily apparent that the margins are negative and adequate. It suffices to report that the margins are not involved by melanoma. It would be difficult to precisely measure the distance of the melanoma from the nearest side margin, and that effort would be of no added clinical value.
nearest side margin. A sharply demarcated small superficial spreading or nevoid melanoma is likely adequately excised with a histopathologically measured rim of normal tissue of 2 mm. An ill-defined lentigo maligna melanoma in situ with skip areas often needs in our experience a rim of 3 mm or more of normal tissue to ensure adequate clearance. Based on our experience with lentigo maligna melanoma in situ (clinical experience with review of cases, which locally persisted/recurred as well as step-sectioning tissue samples of margin with tumor present, but away from the margin), a 3-mm clearance of a 2- to 3-mm-thick slice of tissue usually means that the margin is truly negative and that the risk for histologic sampling error is extremely low. This is in keeping with published observations.16 Accordingly, a recurrence of a lentigo maligna melanoma in situ related to a false-negative margin report is unlikely if the histopathologic clearance was 3 mm or more. If the clearance of a melanoma in situ from the nearest side margin is greater than 3 mm, documenting this clearance may be helpful, but it usually suffices to declare the margin as “negative” or “not involved.” We do not believe that it is necessary to precisely measure obvious wide clearances (Fig. 33.13). For the majority of melanomas (in situ, of invasive to tumor stage pT3 or less) located on the trunk of proximal extremities, the deep margin is usually negative. A full-thickness excision with subcutis should establish sufficient clearance with depth. Accordingly, we do not see any value in an extra effort of measuring the distance of a Clark II or III melanoma to the nearest deep subcutaneous margin. By definition, Clark II or III melanomas are confined to the papillary dermis, and it should be obvious to the surgeon that if deep dermal and subcutaneous tissue was removed, and the margin was reported as negative, the margin clearance should be sufficient. For invasive melanoma, especially those located in the head and neck region, where there are greater limitations to how wide and deep
an excision can be performed, or if the tumor displays neurotropism, the clearance from the deep margin may be a problem, and a narrow margin clearance should be documented in the pathology report to alert the clinician to a higher risk for local recurrence and potential considerations for additional surgical clearance or postoperative radiation treatment. There is limited data on the minimum clearance of invasive melanoma from the nearest deep margin. Based on our experience, if invasive melanoma, especially spindle cell desmoplastic and/or neurotropic melanoma, extends to within less than 3 mm of the deep margin, we recommend documenting this finding and specifying, if possible, where the tumor extends close to the deep margin. With the advances in digital imaging, we envision future pathology reports that will use an image of the tumor to document its relationship to side and deep margins. The image has the added advantage of not only allowing assessment of the margin clearance, if that is wanted, but also conveying information about the anatomic levels involved, the volume, and the growth pattern of the tumor. For a nodular, relatively circumscribed tumor a narrower margin clearance is more likely sufficient to minimize risk for local recurrence, while a wide safety margin is necessary for a diffusely infiltrative tumor.
REFERENCES 1. www.aad.org/practicecenter/quality/clinical-guidelines/melanoma/ surgical-management. 2. www.nccn.org. 3. www.skincancer.org. 4. Thomas JM, et al. Excision margins in high-risk malignant melanoma. N Engl J Med. 2004;350:757–766. 5. Veronesi U, et al. Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm. N Engl J Med. 1988;318:1159–1162. Erratum in: N Engl J Med 1991 Jul 25;325:292. 6. Doepker MP, et al. Is a wider margin (2 cm vs. 1 cm) for a 1.01-2.0 mm melanoma necessary? Ann Surg Oncol. 2016;23:2336–2342. 7. Kunishige JH, Brodland DG, Zitelli JA. Surgical margins for melanoma in situ. J Am Acad Dermatol. 2012;66:438–444. 8. Hazan C, et al. Staged excision for lentigo maligna and lentigo maligna melanoma: a retrospective analysis of 117 cases. J Am Acad Dermatol. 2008;58:142–148. 9. Prieto VG, et al. Are en face frozen sections accurate for diagnosing margin status in melanocytic lesions? Am J Clin Pathol. 2003;120:203–208. 10. Valentín-Nogueras SM, et al. Mohs micrographic surgery using MART-1 immunostain in the treatment of invasive melanoma and melanoma in situ. Dermatol Surg. 2016;42:733–744. 11. Iorizzo LJ 3rd, et al. Importance of vertical pathology of debulking specimens during Mohs micrographic surgery for lentigo maligna and melanoma in situ. Dermatol Surg. 2013;39(3 Pt 1):365–371. 12. Connolly KL, et al. Locally recurrent lentigo maligna and lentigo maligna melanoma: characteristics and time to recurrence after surgery. Dermatol Surg. 2017;43:792–797. 13. Johnson TM, et al. Usefulness of the staged excision for lentigo maligna and lentigo maligna melanoma: the “square” procedure. J Am Acad Dermatol. 1997;37:758–763. 14. Moyer JS, et al. Efficacy of staged excision with permanent section margin control for cutaneous head and neck melanoma. JAMA Dermatol. 2017;153:282–288. 15. Smoller B, et al. Protocol for the examination of specimens from patients with melanoma of the skin. www.cap.org/cancerprotocols. 16. Joyce KM, et al. An assessment of histological margins and recurrence of melanoma in situ. Plast Reconstr Surg Glob Open. 2015;3:e301.